Protein pushes breast cancer cells to metastasize

Using an innovative tool that captures heretofore hidden ways that cells are regulated, scientists have identified a protein that makes breast cancer cells more likely to metastasize. What's more, the protein appears to trigger cancer's spread in part by blocking two other proteins that are normally linked to neurodegeneration, a finding that suggests these two disease processes could have unexpected ties.

The study points to the possibility of new cancer therapies that target this master regulator that helps set metastasis in motion. It was conducted at Rockefeller University in New York, New York, and published in Nature (2014; doi:10.1038/nature13466).

"Although the research is in its very early days, if we learn more about how this regulation works, we may in the future be able to generate drugs that prevent this protein from triggering metastatic disease," said senior author Sohail F. Tavazoie, MD, PhD of Rockefeller.

During the study, Tavazoie and his colleagues measured a new layer of regulation in cancer cells. Rather than examining sequences of DNA, their tool examined both the sequence and the shape of RNA.

It turns out, the shape of an RNA molecule matters. Specifically, some segments of messenger RNA form hairpin loops, which create sites for key proteins to bind to and regulate that RNA, such as telling the cell to destroy it. "These structural differences help determine RNA's fate, by exposing or hiding the binding sites for those key proteins," said co-author Hani Goodarzi, PhD, also of Rockefeller.

In cells prone to metastasis, the scientists found certain RNA hairpin loops that were overrepresented in the sequences of RNAs targeted for destruction. They then identified a protein that binds to those hairpin sequences—TARBP2, known to play a role in the formation of microRNAs. But here, it appears TARBP2 can also act as a master regulator of RNA itself, by binding to multiple sites and causing a suite of changes that lead to metastasis—including the destruction of the RNAs that carry those key binding sites. Indeed, they found that TARBP2 is overexpressed in cells prone to metastasizing, as well as in metastatic human breast tumors themselves.

To determine how TARBP2 carries out its effects, the researchers looked at which genes appear to be downregulated in metastatic cell lines, reasoning that TARBP2 may block these disease suppressors. They made two surprising discoveries: APP, a protein linked to Alzheimer's disease, and ZNF395, which is associated with Huntington's disease, are both downregulated by TARBP2. Cells prone to metastasis showed higher levels of TARBP2 and lower levels of APP and ZNF395; in cancer cells that tend not to spread throughout the body, the opposite was true.

Just what these findings say about the relationship between cancer and neurodegeneration—two of the most common diseases of old age—is still unclear, added Tavazoie.